Modular multichannel microelectrode array and methods of making same

ABSTRACT

Some embodiments of the invention comprise a customizable multichannel microelectrode array with a modular planar microfabricated electrode array attached to a carrier and a high density of recording and/or stimulation electrode sites disposed thereon. Novel methods of making and using same are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims the benefit of priorU.S. patent application Ser. No. 11/545,353, filed Oct. 10, 2006, whichclaims priority based on U.S. Provisional Patent Application No.60/724,501, filed Oct. 7, 2005, which are both hereby incorporated byreference in full.

FIELD OF THE INVENTION

The invention relates to the field of devices and methods used forneural interventions.

BACKGROUND

Neurosurgical interventions are emerging as treatments for a variety ofintractable neurological conditions, including among them, movementdisorders, pain, and epilepsy. Different modalities of treatment thattarget discrete anatomical sites are in current use or in development,including radiofrequency lesioning, chronic electrical stimulation,tissue implantation, and microdialysis. The strategy of theseinterventions is to diminish or enhance the activity of these sites soas to produce a therapeutic effect. In all cases, accurate targeting isessential to obtain an optimal treatment with minimal risk to thepatient.

Targeting is often effected through devices that establish a neuralinterface. Such devices are important for clinical and scientificpurposes. A ‘neural interface’ refers to the interface between a deviceand a targeted region of the nervous system for the purposes ofrecording neural signals, stimulating neurons, and delivering fluidicagents, or combinations of these purposes. A ‘neural interface region’refers to the volume of the nervous system that is recorded from,stimulated, or affected by delivery of the fluidic agent. In general,neural interface regions could extend from as small as 1 micron or lessfrom the device surfaces to several centimeters from the surfaces,depending on the application. ‘Tuning’ the neural interface regionrefers to selectively adjusting the recording, stimulation, or fluiddelivery regions to target specific neural structures.

As only one example, a current method for targeting for placement of adeep brain stimulation (“DBS”) electrode for Parkinson's Diseaseinvolves the use of neurophysiological (functional) mapping of structureboundaries with reference to high quality CT or MRI images of the brain.At present, mapping involves penetrating the computed target structureswith single-channel movable wire microelectrodes to identify theneuronal structure boundaries. Each microelectrode is advanced veryslowly, stopping to examine individual cells and to record the firingfrequency and pattern. When the microelectrode reaches the target brainstructure, a typical change in electrical activity occurs, due to thesustained pattern of discharge of specific neuron types.

In addition to using electrical recording techniques for mapping, macro-or microstimulation (from the same or a second adjacent electrode) canbe used to assess the effects of electrical stimulation on units alongthe trajectory and in the potential target. Specifically, combinedmicrorecording and microstimulation techniques can be used tophysiologically determine the location of both target and non-targetareas deep within the brain. Due to limitations related to theelectrode, which is typically a single-channel device or a number ofsingle-channel devices used together, this mapping procedure is oftentedious, time-consuming, and difficult, which combine to limit itsutilization and effectiveness.

Conventional single-channel electrodes are typically formed from smalldiameter metal wires (e.g., tungsten, stainless steel, platinum). Theseelectrodes are most often formed by electrolytically sharpening ormechanically beveling the wire to a fine tip (<1 micrometer) and theninsulating it, leaving only the tip exposed. Alternatively, microwirescan be formed from pre-insulated fine wires that have been cut to exposethe cross-sectional area at the end of the wire. These types of wiredevices can be converted into electrode arrays by combining multiplewires into an assembly. However, this bundled wire construction createslimitations to establishing selective neural interfaces because thesize, number, and location of electrode sites are intricately related tothe device's size, shape, stiffness, and structural complexity. Suchdevices are also difficult to manufacture to small tolerances on theorder of an electrode site feature size, typically in the range of 1-15microns. The relatively large variability in electrode size and thelimited electrode array configurations of these devices preclude theability to connect groups of electrodes together to selectively tune theneural interface.

As an alternative to bundled wires, multichannel electrode arrays thatutilize wafer-level microfabrication methods employed in thesemiconductor industry have been under development for nearly threedecades (Wise, et al., 2004, Proc. IEEE, 92:72-97) and have been usedfor neurophysiological research. In general, these techniques aresimilar to those used to create integrated circuits and utilize similarsubstrate, conductor, and insulating materials. Fabrication typicallystarts on a wafer substrate, and the electrode features are added usinga number of photolithographically patterned thin-film layers that aredefined by etching. These methods are attractive since they result inreproducible, batch-processed devices that have features defined towithin less than +/−1 micron. Using these methods, an individualelectrode site can be made about as small as the tip of a small wiremicroelectrode, while the microelectrode shank, the portion thatsupports the electrode sites and displaces the tissue, can carrymultiple recording sites and can cross-sectional area and volume that iscomparable to a single wire electrode.

Generally speaking, the fabrication processes for currentmicrofabricated devices impose practical limits on the length of thedevice to about less than 1 cm. Such a device would not be suitable, forexample, for a human deep brain mapping electrode which must penetrateat least 70 mm from the brain surface to target the basal ganglia orthalamus. In addition, these mapping electrodes require extra length ofup to 200 mm for mounting in a stereotactic frame and for connection toexternal instrumentation. Another limitation to microfabricated devicesis that the materials typically used as a substrate are often either toobrittle (e.g. silicon) or too flexible (e.g. polyimide, parylene) toprecisely target particular neural structures.

There are examples of multi-site devices for neural interfacing that donot use wafer level microfabrication techniques but that do employsimilar processing steps such as thin-film metal deposition andsubsequent laser micromachining to define electrode traces on a centralcore. While these devices may provide a high density of sites on asubstrate similar in size to conventional single-channel wires, and theycan be manufactured on substrates that can target human deep brain,there are several desirable characteristics that are absent. First, thedevices are not batch fabricated. In other words, each device must betreated individually to form a plurality of electrode interconnects andsites. Additionally, in many cases, each interconnect as well as eachsite must be individually formed. Second, the array of electrode sitesand interconnects are built up from the structural substrate in a mannerthat generally makes the formation of the electrical features (e.g.sites, traces and connection contacts) closely dependent on the length,shape, and material properties of the substrate. The coupling betweenformation and placement of the electrode sites and the underlyingstructural component limits the ability to group small sites to form amacro site to shape the interface range.

There exist examples of devices used for clinical deep brain mapping,which are designed for intraoperative use only. These consist of asingle microelectrode site that is appropriate in size forneurophysiological mapping. While these electrodes have enabled improvedplacement of deep brain stimulation electrodes, they only offerrecording capability at the tip, limiting the capability to tune theregion with which the device is interfaced.

There are also examples of devices used for clinical DBS, which aredesigned for long-term implantation and functionality. These devices arecomprised of a flexible polymer cylindrical substrate with four metalelectrode contacts (sometimes referred to as “macroelectrodes”). Theseelectrode contacts are configured such that each electrode site isplaced around the perimeter of a flexible substrate to form acylindrical shape. The electrode sites are positioned linearly along theaxis of the cylindrical substrate. Due to the relatively large size ofthis device (including its stimulating surfaces), the small number ofstimulating sites, and the way that it is constructed, this device islimited in its ability to establish tunable neural interface regions.

The ability to record and/or stimulate, for example, through multipleelectrode sites simultaneously has the potential to greatly improve thespeed and accuracy of the mapping procedure. While single siteelectrodes are limited by permitting recording from only a single pointin tissue at a time, electrodes with multiple spatially separaterecording channels would be capable of recording simultaneously frommany points. Recordings may be comprised of spontaneous neuronalactivity, movement-related activity, or evoked activity as a result ofstimulation from nearby sites. Simultaneously sampled recordings couldbe exploited to increase the speed and accuracy by which data areacquired. Electrode arrays that are capable of simultaneously samplingfrom the same neuronal region are also likely to detect regions ofstatistically independent background noise and/or artifacts. Usingadvanced signal processing techniques such as independent componentanalysis, these unwanted signals could be identified and removed,resulting in improvement of the signal-to-noise ratio, and in turnfacilitating neuronal spike discrimination. This technique may alsoreveal signals that were previously hidden within the background noise.Thus, an unmet need remains for a neural interface device that:

-   -   Can be configured to create selective and tunable neural        interface regions over large spatial distances;    -   Establishes high-resolution multi-site interfaces targeted at        all regions of the nervous system (e.g., centrally or        peripherally), including deep brain regions;    -   Establishes multi-modal (e.g., electrical and chemical)        interfaces targeted at all regions of the nervous system        (centrally or peripherally), including deep brain regions;    -   Has a large design space (e.g., site area, site spacing,        substrate shape) to provide customizable devices specific to a        variety of applications;    -   Is capable of supporting a high density of electrode sites on a        substrate/carrier that is the same size or smaller than        conventional single-channel microelectrodes;    -   Is fabricated from biocompatible materials; and    -   Is easily manufactured.

SUMMARY

Without limitation to only embodiments described in this section, theinvention comprises a modular multichannel microelectrode array (also“neuroprobe system”) having a carrier with at least one planarmicroelectrode array attached to the carrier, the planar microelectrodearray comprising a substrate formed separately from the carrier andfurther comprising a plurality of interconnects disposed on thesubstrate between layers of dielectric material, a plurality ofelectrode sites at least some of which are in contact with acorresponding interconnect, and a plurality of bond pads at least someof which are in contact with a respective interconnect, wherein at leastone of the electrode sites is a recording site or a stimulation site.Methods of making and using same are also disclosed herein, as areadditional features of these and other embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described, by way of example only,with reference to the accompanying drawings, in which:

FIG. 1 illustrates the distal and proximal ends of a preferredembodiment of the neuroprobe system

FIG. 2 illustrates the electrode site formation process

FIG. 3 illustrates the method used for folding the polymer arrays toachieve long lengths

FIG. 4 shows electrical recordings from the neuroprobe system acquiredfrom saline and brain tissue.

Other aspects of the invention will be apparent to those skilled in theart after reviewing the drawings and the detailed description below.

DETAILED DESCRIPTION

Without limiting the invention to only those embodiments describedspecifically herein, some embodiments comprise a multichannel neuroprobethat is modular and customizable and that can be used in a variety ofconfigurations for micro- and macro-level interfacing with targetedneural populations. The neuroprobe is comprised of a central carrieronto which a planar multichannel microelectrode array is attached. Thedevice and methods of making same use semiconductor microfabricationtechniques to achieve precise, small features that can be optimized tointerface with specific brain structures, and novel assembly techniquesto convert the microfabricated array into a macro-scale structure thatcan be used to reach a variety of central and peripheral nervous systemregions.

Some embodiments of the invention comprise (FIG. 1):

-   -   1. A cylindrical carrier 1 that can either be rigid or flexible,        solid or hollow, depending on material choice and desired use,        and    -   2. A planar microfabricated electrode array 3 attached to the        carrier 1 that offers a high density of microelectrode sites 5,        7, 9 at the distal end and bonding regions 13 at the proximal        end.

The microelectrode array component can be custom designed to optimallysample (record) and/or selectively activate (stimulate) neuralpopulations. Embodiments comprise the ability to selectively tune thesize and shape of the neural interface region that is to be recordedfrom and/or stimulated. Sites can be tuned for recording, stimulation,or the substrate can include a combination of both types of sites thatcan be used, as one example only, for applications such as impedancemeasurement of tissue (e.g. Siemionow, J. Neurosci. Meth., 2000,96:113-117).

The carrier provides structural support and, in some embodiments,extends the functionality of the device by providing a lumen throughwhich fluids (e.g. those containing pharmaceutical compounds) can bedelivered to targeted structures, and/or by additional function as asingle-channel microelectrode.

In some embodiments, without limitation (FIG. 1), the neuroprobe systemis comprised a planar microelectrode array 3 disposed on an insulatedmetal wire (e.g. tungsten, stainless steel, platinum-iridium) carrier 1.Optionally the distal end of the wire carrier can be sharpened and theinsulation can be removed at the tip 11 to form a conventionalsingle-channel microelectrode. This configuration makes the device adrop-in replacement for current human deep brain mapping electrodes, forexample, with extended functionality (i.e. multichannel recording and/orstimulation). In another embodiment, the planar microelectrode array 3is disposed on a flexible polymeric (e.g. polyimide, silicone) carrier.Optionally the carrier can include a lumen and a port at its distal endthat can be used for targeted drug delivery. This feature allows for theprecise delivery of specific pharmaceutical compounds to localizedregions of the nervous system which could assist, for example, withintraoperative mapping procedures or with long-term therapeutic implantdevices. Optionally a stiffener or stylet is inserted through the lumento facilitate assembly and insertion of the neuroprobe into the targettissue. This stiffener or stylet may be removed after insertion if thedevice is to be used in a permanent manner or if the lumen is to be usedfor drug delivery. If the stiffener or stylet is a sharpened, insulatedmetal wire with the insulation removed at the tip, it can be used as aconventional single-channel microelectrode as previously described.

The planar microelectrode array 3 is comprised of conductiveinterconnects disposed between layers of dielectrics which insulate theinterconnects on top and bottom sides. At least some interconnectsterminate with recording and/or stimulation electrode sites 5, 7, 9 onthe distal end and/or with bond pads 13 for electrical connection toexternal instrumentation and/or hybrid chips on the proximal end. In oneembodiment, the interconnects are metal (e.g. platinum, gold) and thedielectric is a polymer (e.g. polyimide, parylene, PDMS). In anotherembodiment, the interconnects are polysilicon insulated with inorganicdielectrics (e.g. SiO₂, Si₃N₄) and polymer. In another embodiment, theinterconnects are polysilicon insulated with inorganic dielectrics thatare supported below by a silicon substrate. In yet another embodiment,the device is either a silicon or polymer-based structure with electrodesites, interconnects and bond pads as described above, as well as aburied channel for fluid delivery (e.g. Chen, et al., 1997, IEEE Trans.Biomed. Engin., 44:760-769; Takeuchi, et al, Proceeding of IEEEInternational Micro Electro Mechanical Systems (MEMS'04), pp. 208-210(2004)).

Electrode sites and bond pads are formed by opening apertures throughthe top dielectric and depositing and patterning metal (e.g. iridium,platinum, gold). In one embodiment, electrode sites 5, 9 are located onthe distal end of the main body of the planar microelectrode array. Atleast one of these electrode sites 9, for example, can be larger in areaand used as a reference site for recording or stimulation. In anotherembodiment, the array also has electrode sites on “tabs” 7 that projectoff the side of its main body. These tab sites 7 can be used to formring electrodes that wrap around the carrier that can be used forstimulation and/or recording.

The precision, consistency, and reproducibility of the electrode siteson the microelectrode array result in predictable electrical and spatialcharacteristics. These characteristics enable the sites to be grouped ina manner that enables precise, predictable, and selective tuning ofneural interface regions. Some embodiments of the invention comprise twoor more electrode sites grouped to form a larger composite site thatenables tuning the neural interface region for recording and/orstimulation. This grouping of sites can be through intrinsic connectionof the site traces, or it can be through external connections for ‘onthe fly’ tuning

The composite sites can have diverse shapes that are driven by desiredrequirements of the neural interface. For example, a composite site maybe a vertical strip along the array or a horizontal band. It may alsotie together opposing strips to form a contiguous band. Composite sitescan be used to establish one or more tunable neural interface region forthe device. Multiple neural interface regions can be overlapping ornon-overlapping.

The composite sites have utility for recording and/or electricalstimulation. For stimulation, a larger composite site increases theeffective site area to allow increased charge injection whilemaintaining safe electrochemical and biological limits. This willenable, for example, precise current steering to selectively stimulateneural structures. For recording, a composite site can be used to changethe recording selectivity of the device to emphasize, for example, fieldpotential recording over single-unit recordings.

General fabrication techniques of these planar polymer and siliconmicroelectrode arrays are known to those skilled in the art (e.g.,Rousche, et al., IEEE Trans. Biomed. Engin., 48:361-371, Hetke, et al.,1994, IEEE Trans. Biomed. Engin., 41:314-321). In addition, embodimentsof the invention include novel processing and design modifications thatmake the novel planar microelectrode array component, as outlined below.

It is important to keep the width of the planar microelectrode array 3within certain limits so that the assembled neuroprobe system (FIG. 1)is comparable in size to a conventional single-channel microelectrode(e.g. commercially available single-channel deep brain mappingmicroelectrodes are typically less than about 330 microns in diameternear the tip). Yet it is also critical to have the capability to includelarge electrode site 5, 7, 9 areas for some applications. One method tokeep the width minimized is to provide two layers of interconnects, eachlayer being separated by a layer of dielectric. This permits moredensely packed interconnects in a given width. Another method tominimize width involves a novel electrode site formation process.Existing techniques for producing electrode sites on polyimide andparylene substrates use a single step process that involves etching anaperture through the top dielectric to expose the metal site below. Insuch cases, the electrode site is contiguous with the interconnect andthe result is an electrode site that is recessed within the topdielectric. Depending on the desired site area and shape, the metaltypically widens in the region of the site aperture resulting in ascaling of substrate width with electrode site size.

In a polymeric microelectrode array embodiment, without limitation,electrode sites are formed using a three step process which results in asite area that is not limited to or defined by the size of the aperturethrough the top dielectric (FIG. 2). First, a small site aperture isetched through the top dielectric 25 using reactive ion etching (“RIE”).The recess is next filled by electroplating metal (e.g. gold, platinum)27 through a photolithographically defined mask. Finally, metal isdeposited and the electrode site 5 is formed using a conventionallift-off process. As illustrated in FIG. 2, the site 5 is not limited bythe size of the aperture. In fact, it can be much larger than theaperture since it is electrically isolated from underlying interconnects15 by dielectric 25. In addition, it can have virtually any desiredshape. Using this method, for example, at least twelve electrode sitesand associated metal interconnects can be realized on a polyimidesubstrate that is 180 microns wide. The electrode sites can have adiameter of up to the 180 micron substrate width.

Since, before the invention, the length of a planar microelectrode arraywas usually limited by the diameter of the wafer on which it isfabricated (typically 4 or 6 inches in diameter), one of severaltechniques must be used to achieve lengths longer than this. If thearray dielectric material is polyimide, the arrays can be designed in aserpentine shape (FIG. 3) that can be folded into long, straightstructures suitable for mounting on long carriers. The folding processis illustrated in FIG. 3. To perform the first fold, one segment 29 isstabilized while the other segment 31 is flipped under and then crimpeddown at the fold line 21. This crimping process can be performed using apolished surface such as a glass slide or metal block. The second foldis performed by flipping the second segment 31 up and then crimping thedevice at the fold line 23 to achieve the final straight shape. Toensure that the device holds its shape, it can be clamped in place andtempered at about 340° C. for about two hours. Using this method, as oneexample only, a 280 mm long device suitable for recording or stimulatingfrom human deep brain can be realized using four 70 mm long segmentsconnected by three folding regions.

In embodiments of the planar microelectrode array that include parylene,inorganic dielectrics, and/or silicon, the device cannot be folded andcrimped due to material properties. In this case, a two stage device canbe assembled that is comprised of the microelectrode array which willinterface with neural tissue, and a foldable polyimide cable to transfersignals to/from the array. This polyimide cable has the same basicstructure as the polyimide microelectrode array described above but hasbond pads on both its distal (for connecting to the alternativemicroelectrode array) and proximal (for connecting to externalinstrumentation) ends. The two components can be coupled by methodsknown to those of ordinary skill in the art, as one example only, theMicroflex Interconnect Technique outlined in Meyer, et al., 2001, IEEETrans. Adv. Packaging, 24:366-375. Exposed connections can be insulatedby molding the device into a polymeric (e.g. silicone) structure thatwill also serve as the carrier.

As described herein, bond pads are provided at the proximal end of theplanar microelectrode array to provide a method for electricallycontacting the array so that recorded signals can be accessed and/or sothat stimuli may be provided. These pads can be bonded to a connectorassembly (typically a form of printed-circuit board with or withouton-board integrated circuits and a connector), or they can be connecteddirectly to an Application Specific Integrated Circuit (ASIC). Anexample of an application for the latter case would be a multiplexerchip to reduce lead count, or a buffer amplifier to reduce signal lossover long leads.

The ability to combine microelectrode and macroelectrode sites on asingle device allows for sites to be used in a customized mode ofoperation. The positions of the sites selected for stimulation can beadjusted as needed to optimally interface with the neural region ofinterest. This allows for sites to be configured to create an optimizedarrangement of anode and cathode configurations. Additionally, sites canbe used on an individual basis or as a group to effectively form asingle macroelectrode comprised of a plurality of microelectrodes. Thisis of particular importance for stimulation, providing an additionaldegree of freedom when tuning the stimulation parameters in order tooptimally interface with the targeted neural region. For example,electrode sites can be configured in a way that the grouped siteseffectively form a vertical “strip” electrode or alternativelyconfigured to effectively form a “band” electrode. In addition, groupingsites together can increase the charge delivery capability. Thisflexibility allows a user the option to span the range frommicrostimulation to macrostimulation with an increased level of spatialresolution.

Assembly of some embodiments of the neuroprobe system is described here.The proximal end of the folded microelectrode array component and itsassociated connector are first attached to the carrier with a suitablemedical grade epoxy (e.g. Epoxy Technologies 353-NDT). The distal end ofthe microelectrode array component can be temporarily attached to thecarrier using a water soluble epoxy (e.g. Master Bond MB-600) tofacilitate the following step. A double-sided device can be realized byattaching a second array on the opposing side of the carrier). Thedistal end of the microelectrode array/carrier assembly is next threadedinto a shorter length of medical grade micro shrink tube (e.g.polyester, PTFE, FEP). It is threaded through until it emerges from theother end of the shrink tube so that the conductive electrode sites areexposed. The assembly is then heated to activate the shrink tube,holding the microelectrode array and its associated folds tight to thecarrier. The water soluble epoxy that holds the distal end(s) of themicroelectrode array component(s) to the carrier should now be removedby soaking the distal end in water for several seconds.

There are several suitable methods to permanently attach the distal endof the microelectrode array component to the carrier. The first involvesapplication of a very thin layer of medical grade adhesive to thecarrier (e.g. Epoxy Technologies 377). This can be done by one ofseveral methods which include, but are not limited to:

-   -   Dip-coating—In this procedure the distal end of the        microelectrode array is held away from the carrier and the        carrier is dipped into epoxy and pulled back out to leave a thin        layer of epoxy. The microelectrode array is then placed onto        this epoxy. Note that if the carrier is of the hollow tubing        type that the proximal end must be first sealed off to avoid        wicking of epoxy up into the lumen. The seal can be cut off        during one of the final assembly steps.    -   Painting—As an alternative to dip coating which coats the entire        surface, a small tool such as a pulled glass micropipette can be        used to selectively coat the carrier by “painting”.    -   Dispensing using adhesive dispenser—There are a number of        commercially available adhesive dispensers (e.g. EFD 2400) that        dispense microdots or lines of adhesive.

FIG. 4 illustrates the recording functionality of one embodiment of theneuroprobe system comprised of a polyimide microelectrode array attachedto a polyimide tube with a tungsten stylet. The polyimide array wasabout 280 mm long and had recording platinum recording sites that had asurface area of about 1000 microns². The device was evaluated both onthe bench top and in animals. Bench top tests were conducted bydelivering a previously acquired neural recording into saline andsubsequently recording this signal with the neuroprobe system. Arecorded neural (voltage) waveform was converted into a current waveformusing an optically isolated current stimulator. This signal was thendelivered into saline through a bipolar electrode made from twistedplatinum wire (each wire was 200 microns in diameter). Each wire wasinsulated such that only the metal at the tip was exposed to thesolution. The twisted pair was used as the anode and cathode and adistant platinum wire (non-insulated, 500 microns in diameter) was usedas a reference. FIG. 4(A) shows data acquired on a distant channellocated 1 cm from the stimulating source. No discernable spikes werepresent on this channel demonstrating that electrical cross-talk was notpresent across electrical traces. FIG. 4(B) shows data recorded on anelectrode contact located approximately 1 mm from the stimulatingsource. The average noise floor for the electrode contacts tested was 20microV_(p-p). Signal-to-noise ratios on the bench top exceeded 10:1 asseen in FIG. 4(B).

In vivo tests were conducted in anesthetized rats. Neuroprobe systemswere inserted into the barrel cortex of Sprague-Dawley rats. Both localfield potentials and neural spikes were acquired and saved to disk foroffline analysis. FIG. 4(C) shows spike activity acquired on one channelfrom an implanted neuroprobe system. The average noise floor (includingthe neural “hash”) was 30 microV_(p-p). Average signal-to-noise ratioswere approximately 5:1 in recordings collected from rat barrel cortex,as shown in FIG. 4(C).

Each of the references identified herein is hereby incorporated byreference as though fully set forth herein.

While the present invention has been particularly shown and describedwith reference to the foregoing preferred and alternative embodiments,it should be understood by those skilled in the art that variousalternatives to the embodiments of the invention described herein may beemployed in practicing the invention without departing from the spiritand scope of the invention as defined in the following claims. It isintended that the following claims define the scope of the invention andthat the method and apparatus within the scope of these claims and theirequivalents be covered thereby. This description of the invention shouldbe understood to include all novel and non-obvious combinations ofelements described herein, and claims may be presented in this or alater application to any novel and non-obvious combination of theseelements. The foregoing embodiments are illustrative, and no singlefeature or element is essential to all possible combinations that may beclaimed in this or a later application. Where the claims recite “a” or“a first” element of the equivalent thereof, such claims should beunderstood to include incorporation of one or more such elements,neither requiring nor excluding two or more such elements.

1. A method of making a neuroprobe system, comprising the steps of:providing a carrier; providing a flexible planar microelectrode arrayincluding: providing a substrate including a plurality of conductiveinterconnects disposed on the substrate and disposed between layers ofdielectrics; forming a plurality of electrode sites on the substratesuch that at least some electrode sites are in contact with acorresponding interconnect, and forming a plurality of bond pads, atleast some of which are in contact with a respective interconnect;folding the planar microelectrode array; and coupling the planarmicroelectrode array to the carrier.
 2. The method of claim 1, whereinproviding a carrier includes providing a carrier with a lumen.
 3. Themethod of claim 2, wherein providing a carrier with a lumen includesconfiguring the lumen to carry fluid.
 4. The method of claim 2, furtherincluding inserting a stylet into the lumen.
 5. The method of claim 2,further including inserting a wire microelectrode into the lumen.
 6. Themethod of claim 1, wherein providing a flexible planar microelectrodearray includes providing a substrate with a lateral projection having anelectrode site disposed thereon.
 7. The method of claim 6, whereincoupling the planar microelectrode array to the carrier includesattaching the lateral projection radially to the carrier.
 8. The methodof claim 7, wherein folding the planar microelectrode array includeswrapping the lateral projection of the planar microelectrode arrayaround the carrier.
 9. The method of claim 1, wherein providing asubstrate includes providing multiple layers of conductiveinterconnects, each layer being separated by a dielectric layer.
 10. Themethod of claim 1, wherein forming a plurality of electrode sitesincludes opening an aperture in a dielectric layer to form a recess andfilling the recess with a first metal.
 11. The method of claim 10,wherein forming a plurality of electrode sites further includesdepositing a second metal and patterning the second metal to form atleast one electrode site.
 12. The method of claim 11, wherein patterningthe second metal includes patterning at least one electrode site suchthat the electrode site is larger than the aperture.
 13. The method ofclaim 1, wherein providing a flexible planar microelectrode arrayincludes providing a flexible planar microelectrode array in aserpentine shape.
 14. The method of claim 13, wherein folding the planarmicroelectrode array includes folding the planar microelectrode arrayfrom the serpentine shape into a straight shape.
 15. The method of claim14, wherein folding the planar microelectrode array includes crimpingthe planar microelectrode array at one or more fold lines.
 16. Themethod of claim 14, wherein folding the planar microelectrode arrayincludes folding a first segment of the serpentine shape away from asecond segment of the serpentine shape at a first fold line.
 17. Themethod of claim 16, wherein folding the planar microelectrode arrayincludes folding the first segment of the serpentine shape towards thesecond segment of the serpentine shape at a second fold lineapproximately perpendicular to the first fold line, thereby aligning thefirst and second segments in a straight shape.
 18. The method of claim1, wherein forming a plurality of electrode sites includes configuring aplurality of electrode sites to operate as a composite electrode site.19. The method of claim 18, wherein configuring a plurality of electrodesites to operate as a composite electrode site includes grouping aplurality of electrode sites through connections between electrodesites.
 20. The method of claim 1, wherein coupling the planarmicroelectrode array to the carrier includes applying an adhesive to thecarrier.